Glaucoma, which some estimate affects 2 million adults over 40, is an impairment of vision caused by too much fluid pressure within the eye.
Surgical treatment for glaucoma is effective; however, it is expensive and some surgeons will use surgery only as a last resort.
Carbonic anhydrase inhibitors, prescribed orally, work well to treat this disease, but they carry a host of side effects, from nausea to kidney stones.
Glaucoma stems from an excess of fluid behind the cornea, the three-layered tissue that acts as a window to let light enter. Fluid carrying nutrients such as potassium and glucose constantly wash the inside of the cornea to keep it healthy, much as tears wash the outside of the cornea.
In some middle-aged adults, fluids build up faster than can be absorbed back into the blood, for one of two reasons: the ciliary body (a tiny tissue behind the iris) may excrete too much fluid, or the fluid may not drain off at the normal rate.
Either way, the excess fluid damages the optic nerve. At first a glaucoma victim usually experiences a subtle loss of peripheral vision--objects will seem to disappear from certain spots to the side. But glaucoma often leads to middle-age blindness.
Unfortunately, the two approaches to general drug usage in treating glaucoma--topical (dropped into the eye) and oral (through the mouth)--each have a peculiar set of side effects.
To make the long journey, oral drugs must be dosed in very high concentration. One class of drugs, called carbonic anhydrase inhibitors, slow the formation of fluid by inhibiting a chemical reaction at the ciliary body. Along with their well-tested effectiveness comes nausea, tingling in fingers and toes, and other side effects. Oral drugs generally do not, however, cause side effects in the eye.
From the above discussion it can be seen that there is a continuing need for the development of new drugs that can be applied topically in order to avoid systemic affects, and which may at the same time, still be highly effective. This of course necessitates that the compound be one which will, first of all, effectively stimulate a receptor which will provide the correct intraocular pressure, and secondly penetrate the cornea rapidly and distribute well to the active site, i.e. ciliary body of the eye. It goes without saying that compounds which are active as inocular pressure inhibitors, but have limited penetrability across the cornea and into the ciliary body are, as a practical matter, of limited value in developing truly effective topical glaucoma treatments, even though they may have some test activity in vitro, i.e. in a test tube. Put another way, if the compound does not have the correct distribution and penetration properties, its chances of being pharmacologically active when topically applied to an affected eye in patients, are small at best. Thus, it is important, if one is developing effective topical medicaments, that they be active in vitro and that they be active when actually applied to an affected eye from the standpoint of penetrating the cornea and reaching the active site for effective treatment of glaucoma.
Accordingly, it is a primary object of the present invention to provide a new series of compounds, unassociated structurally with those made in the past that have been regarded as likely candidates for topically effective glaucoma treatments with enhanced corneal penetration, ciliary body distribution properties, and which are compounds of quite simplistic chemical structure from the standpoint of their pharmacophore. This latter fact is important in finding the minimum structure necessary to exert a particular pharmacological action, in this case lowering of (intraocular pressure) IOP.
It is another objective of the present invention to prepare new compounds and new treatment methods using those compounds for glaucoma that can be used topically to avoid the undesirable side effects of most systemic treatments.
An even further objective of the present invention is to prepare and use new compounds, differing in structure from those normally regarded as likely candidates for topical actives, which obviously therefore have a new pharmacophore, and therefore open new areas for potential screening for other topically effective candidates.
An even further object of the invention is to prepare a pharmaceutical compositions using these compounds or their biologically active salt forms as effective topical treatments for glaucoma.
The method and manner of accomplishing each of the above objectives, as well as others, will become apparent from the detailed description of the invention which follows hereinafter.